Rev. Bras. Farm. 94 (2): 115-119, 2013
PESQUISA/RESEARCH
Stability of carbamide peroxide in gel formulation as prepared in Brazilian
compounding pharmacies
Estabilidade do peróxido de carbamida na formulação de gel como preparado em farmácias brasileiras de
manipulação
Recebido em 11/07/2012
Aceito em 04/03/2013
1
1
Aina N. Gadanha , Charline R. Rossini , João P. S. Fernandes *
2,3
& Márcio Ferrarini
1,3
1
Universidade Metodista de São Paulo, SP, Brasil
Centro de Ciências Biológicas e da Saúde, Universidade Presbiteriana Mackenzie, SP, Brasil
3
Centro Universitário São Camilo, SP, Brasil
2
SUMMARY
Carbamide peroxide (CP) is a widely used tooth bleaching agent in Brazil. Although commercially available, CP is commonly
synthesized in Brazilian compounding pharmacies to reduce costs. The aim of this work is to evaluate the stability of CP as
raw material and its gel formulation. The CP was synthesized as made in compounding pharmacies, and its purity was
determined by iodometric volumetry using the method described in USP. The prepared CP was maintained at 5 °C, 25 °C, 40
°C (closed flask) and 40 °C (open flask). A 10% CP gel formulation was prepared, and its stability was determined at 5 °C and
40 °C. The raw material was stable at 5 °C in closed flask, and at 40 °C in open flask. The gel was more stable under
refrigeration (5 °C). The prepared CP is stable, and its gel formulation should be stored under refrigeration to maintain its
stability.
Keywords: Drug stability, Tooth bleaching agents, Remedy expiration
RESUMO
O peróxido de carbamida (PC) é um agente de branqueamento dental amplamente utilizado no Brasil. Embora comercialmente
disponível, o CP é normalmente sintetizado em farmácias magistrais visando a redução do custo final da formulação. O
objetivo deste trabalho foi o de avaliar a estabilidade do CP, tanto como matéria-prima quanto na sua formulação magistral de
gel. O PC foi sintetizado seguindo o procedimento usualmente utilizado em farmácias de manipulação e a sua pureza foi
determinada por iodometria, utilizando o método descrito na USP. O CP preparado foi mantido a 5 °C, 25 °C, 40 °C (frasco
fechado) e 40 °C (frasco aberto). Utilizando a mesma matéria prima, uma formulação de gel a 10% foi preparada e a sua
estabilidade foi determinada a 5 °C e 40 °C. A matéria-prima mostrou-se estável em frasco fechado, quando mantida a 5 °C e a
40 °C em frasco aberto. Na forma de gel, a formulação mostrou-se estável sob refrigeração (5 °C).
Palavras-chave: Estabilidade de medicamentos, Clareadores dentários, Prazo de validade de medicamento
INTRODUCTION
Carbamide peroxide (CP) also called urea peroxide is
among the most used dental bleaching agents in Brazilian
dentistry. It is a product from the reaction of hydrogen
peroxide and urea, resulting in a solid with higher stability
than hydrogen peroxide itself (Taliansky, 2005). The
bleaching action results from a chemical oxidative process
involving the hydrogen peroxide and discoloured compo-
nents of enamel pores and dentine, through the formation
of reactive oxygen species (ROS), as peroxide and
hydroxyl anions and free radicals. These species attack and
cleave chemical bonds of chromophores, leading to a
whitening effect (Sulieman, 2008). The urea, in theory, can
help the bleaching process by its decomposition in carbon
dioxide and ammonia, that increases the pH and improve
* Contato: João P. S. Fernandes, Centro de Ciências Biológicas e da Saúde, Universidade Presbiteriana Mackenzie, R. Consolação 930, 01302-907, São Paulo
SP, Brazil – Tel: +55 11 2114 8004, email: [email protected]
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Gadanha et al.
Rev. Bras. Farm. 94 (2): 115-119, 2013
the process (Sun, 2000).
Other uses of CP includes relief of minor inflammation
of gums, oral mucosal surfaces and lips (Tartakow et al.,
1978; Etemadzadeh, 1991), emulsification and dispersion
of ear wax and some formulations for endodontic
treatments use the antiseptic properties of CP during the
chemical-surgical preparation of root canal (Yamazaki et
al., 2010).
Although CP is commercially available, its low
availability in Brazilian market and high cost in
comparison to the starting material encourage the Brazilian
compounding pharmacies to synthesize it when necessary
for dental formulations, since it can be easily obtained and
isolated with good purity and considerable yields. The CP
can be prepared by recrystallization of urea in a 30%
aqueous hydrogen peroxide solution. This method is
widely used and described in literature (Taliansky, 2005;
Lu et al., 1941).
One of the concerns with pharmaceutical formulations
produced in compounding pharmacies is the stability of the
formulation, since the process is made in a laboratorial
scale and usually stability tests are not performed as a
routine or in an appropriate manner.
Considering that the peroxides are relatively unstable,
mainly in aqueous environment, the main objectives of this
work are evaluate the stability of CP as raw material
obtained in Brazilian compounding pharmacies and its gel
formulation intended to be used for dental bleaching.
MATERIALS AND METHODS
All chemicals used in this work were obtained in its
commercially available analytical grade. CP was
synthesized according to the method below.
Synthetic procedure
In a flame-dried flask, were added 103 mL of a 30%
hydrogen peroxide solution (Synth Labs, Diadema, SP,
Brazil) and heated to 45 °C. Thereafter 64 g of urea (Synth
Labs, Diadema, SP, Brazil) and 1.7 g of sodium
pyrophosphate (Synth Labs, Diadema, SP, Brazil)
previously triturated were added to the solution. The
resulting mixture was maintained under stirring in room
temperature overnight. The solid precipitate was filtered
off under reduced pressure in sintered funnel. The
obtained crystals were dried and characterized as CP
according to the literature data.
Purity determination
The purity was determined by iodometric volumetry
using the method described in United States Pharmacopeia
(Pharmacopeial Convention, 2008). About 100 mg of the
CP or equivalent amount of gel, accurately weighted was
transferred to a 500 mL iodine flask with the aid of 25 mL
of water, 5 mL of glacial acetic acid (Carlo Erba Reagents,
Milano, Italy), 2 g of potassium iodide (Synth Labs,
Diadema, SP, Brazil) and 1 drop of ammonium molibdate
(Merck KGaA, Darmstadt, Germany) TS. The flask was
closed and kept in dark for 10 minutes. The liberated
iodine was titrated with 0.1 N sodium thiosulfate (Merck
KGaA, Darmstadt, Germany).
The amount of CP was calculated considering that each
mL of 0.1 N sodium thiosulfate reacts with 4.704 mg of
CP.
Gel preparation
The gel composition was presented in table 1.
The sodium saccharin (Synth Labs, Diadema, SP, Brazil)
and the EDTA (Merck KGaA, Darmstadt, Germany) were
previously dissolved in water and the methylparaben
(Merck KGaA, Darmstadt, Germany) and the mentol
(Synth Labs, Diadema, SP, Brazil) in ethanol. The
carbomer 940 (Lubrizol Advanced Materials, Cleveland,
OH) was dispersed in water with the glycerin (Synth Labs,
Diadema, SP, Brazil) and the pH was adjusted to 7.0 (+/0.2).
The CP was previously triturated and solubilized with
enough amount of water, then added to the gel. The final
product was packaged in 5 mL plastic disposable syringes
as commercially available.
Table 1. Formulae of the CP gel
Component
Carbomer 940
Glycerin
Sodium saccharin
Methylparaben
EDTA
Menthol
Carbamide Peroxide
Purified Water
Ammount
3%
5%
1%
0.15 %
0.1 %
0.1 %
20 %
70.5 mL
Stability test for the raw carbamide peroxide
The sample was divided in 4 groups: (A) that was
maintained refrigerated at 5 °C (+/- 2 °C) in a sealed glass
flask; (B) that was maintained at 25 °C (+/- 2 °C) in a
sealed glass flask; (C) that was maintained at 40 °C (+/- 2
°C) in a sealed glass flask and (D) that was maintained at
40 °C (+/- 2 °C) in an open Petri dish. The CP content was
determinate initially and at up to 50 days after the
preparation.
Stability test for the carbamide peroxide gel
The sample was divided in 2 groups: (E) that was
maintained refrigerated at 5 °C (+/- 2 °C) and (F) that was
maintained at 40 °C (+/- 2 °C). The CP content of the
formulation was determined initially and during 49 days
after the preparation.
RESULTS AND DISCUSSION
The reaction yield for the carbamide peroxide was
48.9%, with average purity of 97.1% (figure 1). The CP
content in the crystals determinate during the test is shown
in the table 2. The CP contents in the gels during the
stability test are shown in table 3.
CP is a complex formed between urea and hydrogen
peroxide. There are several methodologies described in
literature to prepare CP, most of them deposited as patents.
However, these methodologies are based in a spontaneous
complexation reaction between urea and hydrogen
peroxide in solution (Taliansky, 2005). The crystal of CP
was studied to determine the structure of the complex (Lu
et al., 1941). This complex is sufficient stable to provide
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Gadanha et al.
controlled release of hydrogen peroxide (Gonsalves et al.,
1991), becoming CP a suitable agent for several uses, as
oxidizing agent in chemical reactions (Taliansky, 2005;
Gonsalves et al., 1991; Yu et al., 2008), as antimicrobial
and disinfectant agent (Bentley et al., 1995; Lai et al.,
2003; Lazarchik & Haywood, 2010), and as bleaching
agent in cosmetics and pharmaceutical products (Kowitz et
al., 1991; Fasanaro, 1992; Mokhlis et al., 2000).
Figure 1. CP crystals obtained from synthetic procedure.
Table 2. CP content (expressed in % w/w) in the samples
A (5 °C), B (25 °C), C (40 °C) and D (40 °C – open flask),
during the stability test.
CP content (%)
Day
A
B
C
D
0
98.9
96.9
96.9
96.9
3
97.4
96.0
96.5
96.3
6
97.0
95.7
81.7
n.d.
13
96.7
95.6
21.2
n.d.
20
96.0
93.8
0.1
95.7
31
96.0
77.1
n.d.
95.0
48
95.3
71.1
n.d.
94.5
n.d. – not determined.
Table 3. CP content (expressed in % w/w) in the samples
E (5 °C) and F (40 °C), during the stability test.
CP content (%)
Day
E
F
0
20.1
20.3
4
19.4
20.2
7
19.3
20.3
11
19.5
19.2
14
19.9
18.9
18
19.7
18.1
21
19.5
18.0
32
19.5
17.7
49
19.4
16.8
Although CP is commercially available in preparations
for tooth bleaching as dental gels, several dentists in Brazil
use compounding pharmacies services as an economical
alternative or even to formulate products like Endo-PTC.
However, stability issues were always a question in those
formulations, since stability tests are not performed on
these establishments. Thus, compounded products are very
criticized, due to poor quality control and to the stability of
the formulations. There are several reports of lack of
Rev. Bras. Farm. 94 (2): 115-119, 2013
quality profiles in compounded products in literature
(Pissatto et al., 2006; Scheshowitsch et al., 2007; Baracat
et al., 2009). Despite this, the evaluation of compounded
formulations of CP is necessary to establish the benefits
and/or problems of this kind of preparation.
Home bleaching treatment is preferred by patients and
professionals when compared to the in-office method
because the former technique required less chair time, in
spite of the in-office method being under the dentist’s
control and less expensive. Home bleaching is a method
whereby the patient fills a custom-designed tray with
bleaching material (10% to 20% carbamide peroxide)
(Auschill et al., 2005), which can be obtained in
compounding pharmacies or as industrialized product,
being the former cheaper. When purchasing the bleaching
agent, price might be a determining factor in the choice of
the product to be applied. Sometimes, the patient does not
take into consideration the quality of the formulation to be
used (Martin et al., 2007).
Martin et al. (2007), analyzing the concentrations of CP
in 100 samples of 16% carbamide peroxide gel from 5
sources, being 4 compounding pharmacies and one
industrialized product, found levels from 7.8 to 21.8 % of
CP (48.8 to 136.2 % of the declared value). In this work,
the CP levels had a wide variation and maybe stability
could play an important role to explain these findings.
In the stability test of the CP, the predicted decomposition
reaction would be as shown in figure 2. During the oxygen
and water formation, various reactive intermediates are
formed, being the basis of antimicrobial and bleaching
activities of hydrogen peroxide and, hence, CP.
Figure 2. Chemical decomposition of CP in hydrogen
peroxide.
In the early stages of the test, all samples of the raw
material showed low degradation rates, but between the
3rd and 6th day, the sample C assumed a different
behavior. The crystals got a wet aspect, maybe indicating
degradation in some extend. The formed water was able to
dissolve some of the CP thus accelerating the degradation
rate. Same situation was observed with the sample B after
30 days in stability test. The figure 3 shows the
degradation profiles of the samples A, B, C and D.
The CP amounts in samples A and D had lower
degradation rates, showing better stability for 48 days and
loosing, respectively, 1.65% and 2.47% of its original
amount. As sample A was maintained under refrigeration
(5 °C), the degradation rate was lower than samples B and
C. However, sample D showed relative stability even in
higher temperature (40 °C). It could be attributed to the
water evaporation, since it was maintained in an open
flask. According to the results is reasonable to assume that
the CP synthesized by the method described in this work is
stable, under refrigeration, for 30 days after its preparation.
However, as samples A, B and C were maintained in
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Gadanha et al.
closed flask, maybe these samples could be the same
behavior of sample D, if it were maintained in open flask.
Figure. 3. Content of CP in the raw material samples A, B,
C and D, expressed as % (w/w) versus days in stability
test.
As can be observed in figure 2, the water formation is
due to CP degradation. The liquid water is formed in an
extension capable to dissolve more CP of the sample,
changing the degradation kinetics profile from that
observed in solid state (more stable) to a kinetics of
solution state (more reactive). Moreover, is widely known
that the higher is the temperature, the higher is the velocity
of chemical reactions. Regarding this, the differences
between samples C and D can be rationalized. As sample
C was maintained in higher temperature and in closed
recipient, the formed water was condensed and kept with
the sample, different to the condition in sample D, where
the water was able to evaporate to the air.
The stability definition assumes that the shelf live is
determined as the time were the original amount of the
active ingredient decays 10% (Woolfe & Worthington,
1974; Connors et al., 1986). In practical terms, the
pharmaceutical industry considers lower values to
determine the expiry date of the products, since 10% loss
is a considerable limit. In the gel samples E and F, based
on this criteria, the linear regression of the data gives 100
days of shelf life for the sample E (5 °C) and 24 days for
sample F (40 °C), corroborating with the data obtained for
the stability of the raw material. As the gel formulation
contain high amount of water, the CP degradation rate
seems to be higher. Figure 4 shows the content of CP in
the samples E and F, the linear regression of the data and
the correlation coefficient for the regression.
Rev. Bras. Farm. 94 (2): 115-119, 2013
The influence of temperature in degradation of CP can
be also observed in the samples E and F, where CP is
introduced in a gel. In this condition, CP is dissolved in gel
water, and its chemical behavior follows that observed in
raw material in presence of the condensed water (sample
C) with the difference that the lower concentration and the
restricted diffusion of the formed oxygen affects the
degradation velocity.
Auschill et al. (2005) verified the higher the
concentration of the bleaching agents, the faster the stain is
removed. Bleaching speed is related to the peroxide
concentration and is time dependant (Martin et al., 2007).
A previous study showed that a 15% concentration of CP
resulted in a faster and greater color change than 10%
concentration during the treatment period in the first 2
weeks (Matis et al., 2000). Thereby, the conditions of
storage of the CP gel can influence in the clinical response
due to degradation of active ingredient. The best storage
conditions verified in this work is under refrigeration,
since its shelf life is longer when compared to the storage
in higher temperatures.
In summary, although CP is stable as raw material as
obtained in the described method, its gel formulation
prepared in compounding pharmacies should be storage in
a properly manner to ensure the adequate clinical response.
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